Agency Response Letter GRAS Notice No. GRN 000492

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CFSAN/Office of Food Additive Safety

June 24, 2014

Fernando Fogeda Calderon
Vitae Naturals
C/ Gutemberg 356 Poligono Torrehierro
45614 Talavera de la Reina

Re: GRAS Notice No. GRN 000492

Dear Mr. Calderon:

The Food and Drug Administration (FDA) is responding to the notice, dated December 9, 2013, that you submitted in accordance with the agency’s proposed regulation, proposed 21 CFR 170.36 (62 FR 18938; April 17, 1997; Substances Generally Recognized as Safe (GRAS); the GRAS proposal). FDA received the notice on December 17, 2013, filed it on December 20, 2013, and designated it as GRAS Notice No. GRN 000492.

The subjects of the notice are phytosterols and phytosterol esters formulations (PPEF). The notice informs FDA of the view of Vitae Naturals that PPEF are GRAS, through scientific procedures, for use as ingredients in baked goods and baking mixes; beverages and beverage bases; breakfast cereals; cheeses; coffee and tea; condiments and relishes; dairy product analogs; egg products; fats and oils; fish products; frozen dairy desserts and mixes; grain products and pastas; gravies and sauces; hard candy; soft candy; herbs, seeds, spices, seasonings, blends, extracts, and flavorings; jams and jellies; whole and skim milk; milk products; nuts and nut products; plant protein products; processed fruits and fruit juices; processed vegetables and vegetables juices; snack foods; and soups and soup mixes at levels of 0.5 to 1.0 gram (g)/serving.(1)

Our use of “phytosterols and phytosterol esters formulations” or “PPEF” in this letter should not be considered an endorsement or recommendation of that term as an appropriate common or usual name for the purpose of declaring the substance in the ingredient statement of foods that contain that ingredient. Title 21 CFR 101.4 states that all ingredients must be declared by their common or usual name. In addition, 21 CFR 102.5 outlines general principles to use when establishing common or usual names for nonstandardized foods. Issues associated with labeling and the appropriate common or usual name of a food are the responsibility of the Office of Nutrition, Labeling, and Dietary Supplements in the Center for Food Safety and Applied Nutrition.

As part of its notice, Vitae Naturals includes the report of a panel of individuals (Vitae Naturals's GRAS panel) that evaluated the data and information that are the basis for Vitae Naturals’s GRAS determination. Vitae Naturals considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Vitae Naturals’s GRAS panel evaluated the composition and identity, methods of manufacture, product specifications, and estimates of dietary exposure; as well as published toxicological studies for PPEF. Based on this review, Vitae Naturals’ GRAS panel concluded that PPEF, produced consistent with current good manufacturing practice (cGMP) and meeting purity and established food grade specifications, are GRAS under the conditions of its intended use.

Vitae Naturals describes PPEF as consisting of phytosterols isolated from soybean oil, pine trees, or tall oil, which may be esterified with vegetable oil-derived fatty acids (such as sunflower and rapeseed oil). The major phytosterols and phytostanols in PPEF are β-sitosterol, β-sitostanol, campesterol, campestanol, stigmasterol, and brassicasterol. Vitae Naturals describes three formulations of phytosterols, including a free phytosterol product that is a white, yellowish powder; a water dispersible free phytosterol product that is also a white, yellowish powder; and a phytosterol ester product that is a light yellow viscous liquid.

Vitae Naturals discusses the method of manufacture for PPEF, which are manufactured as three products. Vitae Naturals states that all processes in manufacturing are commonly employed practices of the food industry for production of fats and oils and are in accordance with cGMP using food grade ingredients and processing aids. Free phytosterols are isolated from by-products of soybean oil refining or pine tree wood pulp processing. The phytosterols are isolated using distillation and then purified by crystallization. The resulting crystals are washed with solvent, centrifuged, and then ground to produce the free phytosterol product (PPEF-product 1). The water dispersible free phytosterol product is produced by mixing the free phytosterol product with maltodextrin and sucrose palmitate and is then emulsified, homogenized, filtered, and finally spray-dried (PPEF-product 2). The phytosterol esters product is produced by direct esterification of the phytosterol product with fatty acids derived from vegetable oil (including sunflower or rapeseed oil). Following esterification, the product is distilled and purified using activated charcoal and subsequent filtration (PPEF-product 3). Vitae Naturals states that ascorbyl palmitate and mixed tocopherols are used as antioxidants during the production process for the phytosterol esters product.

Vitae Naturals provides specifications for the three PPEF. Specifications for the free phytosterols, the water dispersible free phytosterols, and the phytosterol esters include total sterols (≥95%, 85 to 95%, and ≥60%, respectively), free sterols (≥95%, 85 to 95%, and ≤2%, respectively), free sterols and sterol esters (≥99% for the esterified form), moisture (≤4%, for each), lead (≤0.1 milligram/kilogram (mg/kg), for each), arsenic (≤3 mg/kg, for each), hexane and/or methanol (< 50 mg/kg, free phytosterol form only), and ash (≤0.1%, for each). Specifications for the free phytosterols product and the phytosterol esters product includes maximum content of β-sitosterol (<80%), campesterol (<40%), stigmasterol (<30%), brassicasterol (<3%), campestanol (<5%), β-sitostanol (<15%), and other sterol/stanols (<3%). Specifications for all PPEF also include limits on microbial contaminants.

Vitae Naturals discusses stability studies conducted with PPEF and concludes that the free phytosterol formulations are stable for at least 48 months under ambient temperature storage conditions and for at least 6 months under accelerated conditions (40°C). The esterified formulation is stable for at least 12 months under ambient temperature storage conditions and for at least 6 months at 40°C.

Vitae Naturals discusses the dietary exposure to PPEF from the intended use in food and by the total U.S. population. Vitae Naturals notes that exposure to phytosterols and phytosterol esters in the U.S. population was previously estimated using the National Center for Health Statistics’ 2003-2004 and 2005-2006 National Health and Nutrition Examination Surveys (NHANES). However, the notifier states that this estimate did not include existing uses in plant protein products. Vitae Naturals estimates the mean and 90th percentile daily exposure to phytosterols at 6.6 g/person/day (120 mg/kg body weight (bw)/day), and 11.0 g/person/day (244 mg/kg bw/day), respectively. Vitae Naturals intends that PPEF are substitutional for previously notified phytosterol and phytosterol esters (GRN 000398), therefore, the use of PPEF described in GRN 000492 will not increase dietary exposure to phytosterols. In addition, Vitae Naturals notes that the uses of PPEF are self-limiting due to the need to maintain the flavor and texture of the foods to which the ingredient is added.

Vitae Naturals considers the effects of increasing the use level in plant protein products from 0.5 to 0.75 g/serving and from using more recent data from NHANES (2009-2010). Vitae Naturals concludes that the dietary exposure to PPEF from the intended use in plant protein products will not impact the overall exposure for the following reasons: 1) only 2.4% of total population was identified as potential consumers of plant protein products; and 2) the intended use in plant protein products would serve as an alternative source of phytosterols beyond other phytosterol containing food products currently marketed.

Vitae Naturals provides an updated literature review of published toxicological studies for phytosterols through July 2012. Vitae Naturals reports that many published animal studies (including subchronic, reproductive, developmental, and teratogenic) are available and were reviewed; no adverse effects were observed at 4200 mg vegetable oil phytosterols/kg bw/day, the highest level tested. In addition, Vitae Naturals discusses that many published human clinical studies have been completed, which showed no adverse effects at dietary exposures of up to 30 g/person/day phytosterols. Vitae Naturals points out that a variety of different vegetable oil- and tall oil-derived phytosterol ingredients have been the subjects of 13 previous GRAS notices (GRN Nos. 000039, 000048, 000053, 000061, 000112, 000176, 000177, 000181, 000206, 000250, 000335, 000387, and 000398), where FDA had no questions about the GRAS status of the intended uses of phytosterols described in those notices. Finally, Vitae Naturals notes that the safety of phytosterol ingredients in food has been successfully reviewed by various scientific bodies world-wide, including Health Canada, European Scientific Committee on Food, and Food Standards Australia New Zealand. Vitae Naturals concludes from the totality of the supporting information that PPEF are GRAS under the intended conditions of use.

Standards of Identity

In the notice, Vitae Naturals states its intention to use PPEF in several food categories, including foods for which standards of identity exist, located in Title 21 of the Code of Federal Regulations. We note that an ingredient that is lawfully added to food products may be used in a standardized food only if it is permitted by the applicable standard of identity.

Section 301(ll) of the Federal Food, Drug, and Cosmetic Act (FD&C Act)

The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the FD&C Act to, among other things, add section 301(ll). Section 301(ll) of the FD&C Act prohibits the introduction or delivery for introduction into interstate commerce of any food that contains a drug approved under section 505 of the FD&C Act, a biological product licensed under section 351 of the Public Health Service Act, or a drug or a biological product for which substantial clinical investigations have been instituted and their existence made public, unless one of the exemptions in section 301(ll)(1)-(4) applies. In its review of Vitae Naturals’s notice that PPEF are GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing PPEF. Accordingly, this response should not be construed to be a statement that foods that contain PPEF, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).


Based on the information provided by Vitae Naturals, as well as other information available to FDA, the agency has no questions at this time regarding Vitae Naturals’ conclusion that PPEF are GRAS under the intended conditions of use. The agency has not, however, made its own determination regarding the GRAS status of the subject use of phytosterols and phytosterol esters. As always, it is the continuing responsibility of Vitae Naturals to ensure that food ingredients that the firm markets are safe, and are otherwise in compliance with all applicable legal and regulatory requirements.

In accordance with proposed 21 CFR 170.36(f), a copy of the text of this letter responding to GRN 000492, as well as a copy of the information in this notice that conforms to the information in the GRAS exemption claim (proposed 21 CFR 170.36(c)(1)), is available for public review and copying at




Dennis M. Keefe, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition

(1)Vitae Naturals states that PPEF are intended for use in the same food and beverage products at the same levels previously notified in GRN 000398 as well as in plant protein products at a level of 0.75 g/serving, which represents a 50% increase from levels previously notified in GRN 000387.

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